Malignant mesotheliomas in man are associated with asbestos exposure. Although customarily rare, these tumors are dramatically increasing in prevalence in our population. Rats inoculated by the intrapleural and intraperitoneal routes with asbestos of several different types develop lesions which strikingly resemble the human cancers after latency periods of 6 to 24 months. In work supported by this grant, we characterized these lesions and initiated studies to elucidate the pathogenesis of the neoplasm. The proposed research will attempt to develop a model of carcinogenesis originating in the granuloma which forms in and around the accumulations of asbestos that develop after thoracic inoculation of asbestos. Attempts will be made to determine whether or not asbestos-laden macrophages generate oxygen metabolites and damage the chromosomes or the mitotic spindle as a result. Efforts will be made to demonstrate the release of growth factors elicited by the macrophages of the granuloma and their effect on presumptive progenitor cells of the mesothelioma. The outcome of these studies will support or refute the hypothesis that pro-growth substances stimulate their replication in the course of multistage carcinogenesis. Additional work will attempt to demonstrate the presence of premalignant and malignant cells in the reactive tissue mass which forms in and around granulomas in the cavities of animals. Finally, efforts will be made to determine the possible role of proto-oncogenes in the genesis of the tumors and the utility of these genes as markers for identifying transformation of the mesothelial cell or its precursor. These studies are designed to elucidate mechanisms of carcinogenesis for this unique and poorly understood tumor, based on the notion that its pathogenesis may be an example of foreign body carcinogenesis.